HIV persists throughout deep tissues with repopulation from multiple anatomical sources

Journal of Clinical Investigation, Journal Year: 2020, Volume and Issue: 130(4), P. 1699 - 1712

Published: Jan. 7, 2020

BACKGROUND. Understanding HIV dynamics across the human body is important for cure efforts. This goal has been hampered by technical difficulties and challenge of obtaining fresh tissues.

Language: Английский

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Macrophages but not Astrocytes Harbor HIV DNA in the Brains of HIV-1-Infected Aviremic Individuals on Suppressive Antiretroviral Therapy

Journal of Neuroimmune Pharmacology, Journal Year: 2018, Volume and Issue: 14(1), P. 110 - 119

Published: Sept. 7, 2018

The question of whether the human brain is an anatomical site persistent HIV-1 infection during suppressive antiretroviral therapy (ART) critical, but remains unanswered. presence virus in brains HIV patients whose viral load effectively suppressed would demonstrate not only potential for CNS to act as reservoir, also urgent need understand factors contributing behind blood-brain barrier. Here, we investigated first time cells harboring DNA and RNA from subjects with undetectable plasma sustained suppression, identified by National NeuroAIDS Tissue Consortium. Using new, highly sensitive situ hybridization techniques, RNAscope DNAscope, combination immunohistochemistry, were able detect all virally cases found that macrophages microglia, astrocytes, brain. This study demonstrated reservoirs persist macrophages/microglia ART, which cure/treatment strategies will focus on targeting.

Language: Английский

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Curing HIV: Seeking to Target and Clear Persistent Infection

Cell, Journal Year: 2020, Volume and Issue: 181(1), P. 189 - 206

Published: March 26, 2020

Language: Английский

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Pathogenesis of HIV-Related Lung Disease: Immunity, Infection, and Inflammation

Physiological Reviews, Journal Year: 2019, Volume and Issue: 100(2), P. 603 - 632

Published: Oct. 10, 2019

Despite anti-retroviral therapy (ART), human immunodeficiency virus-1 (HIV)-related pulmonary disease continues to be a major cause of morbidity and mortality for people living with HIV (PLWH). The spectrum lung diseases has changed from acute opportunistic infections resulting in death chronic those access ART. Chronic immune activation suppression can result impairment innate immunity progressive loss T cell B functionality aberrant cytokine chemokine responses systemically as well the lung. detected lungs PLWH profound effects on cellular functions. In addition, HIV-related injury occur secondary number mechanisms including altered systemic inflammatory pathways, viral persistence lung, oxidative stress additive smoke exposure, microbial translocation, alterations gut microbiome. Although ART had HIV, impact immunology still needs fully elucidated. Understanding by which continue is critical development new preventive therapeutic strategies improve health PLWH.

Language: Английский

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HIV-1 TAT-mediated microglial activation: role of mitochondrial dysfunction and defective mitophagy

Autophagy, Journal Year: 2018, Volume and Issue: 14(9), P. 1596 - 1619

Published: July 3, 2018

ABSTRACT While the advent of combination antiretroviral therapy (cART) has dramatically increased life expectancy HIV-1 infected individuals, paradoxically, however, prevalence HIV-1-associated neurocognitive disorders is on rise. Based premise that cytotoxic protein, transactivator transcription (TAT), a known activator glial cells found to persist in central nervous system (CNS) despite cART, we sought explore role defective mitophagy TAT-mediated microglial activation. Our results demonstrated exposure mouse primary microglia TAT resulted cellular activation involving altered mitochondrial membrane potential was accompanied by accumulation damaged mitochondria. Exposure expression signaling proteins, such as PINK1, PRKN, and DNM1L, with concomitant increase formation autophagosomes, evidenced BECN1 MAP1LC3B-II. Intriguingly, also SQSTM1, signifying thereby possible blockade flux, leading, turn, mitophagosomes. Interestingly, associated decreased rate extracellular acidification oxygen consumption proinflammatory cytokines, Tnf, Il1b, Il6. leading further validated vivo brains transgenic rats. In conclusion, activates increasing damage via mitophagy. Abbreviations: 3-MA: 3-methyladenine; Δψm: potential; ACTB: actin, beta; AIF1: allograft inflammatory factor 1; ATP: adenosine triphosphate; BAF: bafilomycin A1; BECN1: beclin 1, autophagy related; cART: combined therapy; CNS: system; DNM1L: dynamin 1 like; DMEM: Dulbecco modified Eagle medium; DAPI: 4,6-diamidino-2-phenylindole‎; ECAR: rate; FBS: fetal bovine serum; FCCP: trifluoromethoxy carbonylcyanide phenylhydrazone; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HAND: disorders; TAT: human immunodeficiency virus-1 transcription; IL1B: interleukin IL6: 6; ITGAM: integrin subunit alpha M; MAP1LC3B: microtubule-associated protein light chain 3 mPMs: cells; MRC: maximal respiratory capacity; mt-CO1: mitochondrially encoded cytochrome c oxidase; mt-ND6: NADH:ubiquinone oxidoreductase core NFKB1: nuclear kappa B NLRP3: NLR family pyrin domain containing 3; OCR: PBS: phosphate-buffered saline; PINK1: PTEN induced putative kinase PRKN: parkin RBR E3 ubiquitin ligase; ROS: reactive species; siRNA: small interfering RNA; SQSTM1: sequestosome TNF: tumor necrosis

Language: Английский

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Long-term persistence and function of hematopoietic stem cell-derived chimeric antigen receptor T cells in a nonhuman primate model of HIV/AIDS

PLoS Pathogens, Journal Year: 2017, Volume and Issue: 13(12), P. e1006753 - e1006753

Published: Dec. 28, 2017

Chimeric Antigen Receptor (CAR) T-cells have emerged as a powerful immunotherapy for various forms of cancer and show promise in treating HIV-1 infection. However, significant limitations are persistence whether peripheral T cell-based products can respond to malignant or infected cells that may reappear months years after treatment remains unclear. Hematopoietic Stem/Progenitor Cells (HSPCs) capable long-term engraftment the potential overcome these limitations. Here, we report use protective CD4 chimeric antigen receptor (C46CD4CAR) redirect HSPC-derived against simian/human immunodeficiency virus (SHIV) infection pigtail macaques. CAR-containing persisted more than 2 without any measurable toxicity were multilineage engraftment. Combination antiretroviral therapy (cART) followed by cART withdrawal resulted lower viral rebound CAR animals relative controls, demonstrated an immune memory-like response. We found CAR-expressing multiple lymphoid tissues, decreased tissue-associated SHIV RNA levels, substantially higher CD4/CD8 ratios gut compared controls. These results surveillance. This study demonstrates first time safety feasibility HSPC-based large animal preclinical model.

Language: Английский

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Persistent HIV-infected cells in cerebrospinal fluid are associated with poorer neurocognitive performance

Journal of Clinical Investigation, Journal Year: 2019, Volume and Issue: 129(8), P. 3339 - 3346

Published: July 14, 2019

BACKGROUND. Persistence of HIV in sanctuary sites despite antiretroviral therapy (ART) presents a barrier to remission and may affect neurocognitive function. We assessed persistence cerebrospinal fluid (CSF) associations with inflammation performance during long-term ART.

Language: Английский

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The multifaceted nature of HIV latency

Journal of Clinical Investigation, Journal Year: 2020, Volume and Issue: 130(7), P. 3381 - 3390

Published: June 30, 2020

Although antiretroviral therapies (ARTs) potently inhibit HIV replication, they do not eradicate the virus. persists in cellular and anatomical reservoirs that show minimal decay during ART. A large number of studies conducted past 20 years have shown a small pool cells harboring integrated replication-competent viral genomes. The majority these produce particles constitute what is referred to as latent reservoir infection. Therefore, although considered typical virus, it can establish state nonproductive infection under rare circumstances, particularly memory CD4+ T cells, which represent main barrier eradication. While was originally thought latently infected largely composed transcriptionally silent genomes, recent evidence indicates several blocks contribute cells. Here, we describe virological immunological factors play role establishment persistence review current approaches aimed at eliminating reservoir.

Language: Английский

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Intact HIV Proviruses Persist in the Brain Despite Viral Suppression with ART

Annals of Neurology, Journal Year: 2022, Volume and Issue: 92(4), P. 532 - 544

Published: July 22, 2022

Human immunodeficiency virus (HIV) persistence in blood and tissue reservoirs, including the brain, is a major barrier to HIV cure possible cause of comorbid disease. However, size replication competent nature central nervous system (CNS) reservoir unclear. Here, we used intact proviral DNA assay (IPDA) provide first quantitative assessment defective brain people with (PWH).Total, intact, proviruses were measured autopsy frontal lobe from viremic (n = 18) or virologically suppressed 12) PWH. Total intact/defective by detection pol IPDA, respectively, through use droplet digital polymerase chain reaction (ddPCR). HIV-seronegative individuals included as controls 6).Total was present at similar levels tissues untreated antiretroviral (ART)-suppressed (median 22.3 vs 26.2 copies/106 cells), reflecting stable CNS that persists despite therapy. Furthermore, 8 10 6 9 virally PWH also harbored (4.63 12.7 cells). Viral reservoirs matched lymphoid composition and/or proviruses, albeit lower brain. Importantly, resident CD68+ myeloid cells DNA, directly showing presence reservoir.Our results demonstrate evidence for an potentially ANN NEUROL 2022;92:532-544.

Language: Английский

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EcoHIV infection of mice establishes latent viral reservoirs in T cells and active viral reservoirs in macrophages that are sufficient for induction of neurocognitive impairment

PLoS Pathogens, Journal Year: 2018, Volume and Issue: 14(6), P. e1007061 - e1007061

Published: June 7, 2018

Suppression of HIV replication by antiretroviral therapy (ART) or host immunity can prevent AIDS but not other HIV-associated conditions including neurocognitive impairment (HIV-NCI). Pathogenesis in HIV-suppressed individuals has been attributed to reservoirs latent-inducible virus resting CD4+ T cells. Macrophages are persistently infected with their role as vivo fully explored. Here we show that infection conventional mice chimeric HIV, EcoHIV, reproduces physiological for development disease people on ART immunocompetence, stable suppression replication, persistence integrated, replication-competent cells and macrophages, manifestation learning memory deficits behavioral tests, termed here murine HIV-NCI. EcoHIV established latent lymphocytes chronically-infected could be induced epigenetic modulators ex mice. In contrast, macrophages expressed constitutively up 16 months; leukemia (MLV), the donor gp80 envelope did infect macrophages. Both MLV were found brain tissue only NCI. Murine HIV-NCI was prevented prophylaxis once neither persistent nor NCI reversed long-acting therapy. EcoHIV-infected, athymic more permissive than wild-type mice, suffered cognitive dysfunction, well increased numbers monocytes infiltrating brain. Our results suggest an important expressing neuropathogenesis hosts suppressed replication.

Language: Английский

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